Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet

Michelle Lee, Andrea Kim, Streamson C. Chua, Jr., Silvana Obici, Sharon L. Wardlaw

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH 2-terminal POMC transgene that includes α- and γ3-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume293
Issue number1
DOIs
StatePublished - Jul 2007

Fingerprint

Melanocyte-Stimulating Hormones
High Fat Diet
Nutrition
Fats
Fat-Restricted Diet
Transgenes
Obesity
Melanocortins
Diet
Chemical activation
Glucose
Pro-Opiomelanocortin
Indirect Calorimetry
Liver
Adiposity
Corticosterone
Oxygen Consumption
Energy Metabolism
Weight Gain
Adipose Tissue

Keywords

  • Diabetes
  • Hepatic steatosis
  • Melanocortins
  • Melanocyte-stimulating hormone
  • Obesity
  • Proopiomelanocortin

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. / Lee, Michelle; Kim, Andrea; Chua, Jr., Streamson C.; Obici, Silvana; Wardlaw, Sharon L.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 293, No. 1, 07.2007.

Research output: Contribution to journalArticle

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abstract = "To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH 2-terminal POMC transgene that includes α- and γ3-MSH were studied on either a 10{\%} low-fat diet (LFD) or 45{\%} high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.",
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